Project Summary/Abstract Impairment of neuronal microtubules resulting from hyper-phosphorylation of the tau proteins is implicated in many disease pathologies including Alzheimer's disease (AD), Parkinson disease and other neurological disorders. However, there techniques. (PET) indicates neurodegeneration way are no reliable noninvasive methods to quantify microtubules using clinical imaging key unanswered question is whether the quantitative nature of Positron Emission Tomography harnessed to measure in vivo concentrations of microtubules. Increasing scientific evidence microtubule stabilizing agents provides protective benefits against the deleterious effects of in treating AD. However, quantifying these protective benefits is difficult, since there is no to directly probe their interactions with microtubules. A can be that Our goal is to develop in vivo imaging of microtubules using our novel PET probes, at all stages of AD progression. Thus we propose 3 Specific Aims based on our strong preliminary data. In Aim 1, we will determine the relationship between microtubule integrity and amyloid ? pathology by performing longitudinal microPET/CT imaging of microtubules with [11C]MPC-6827 and amyloid ? imaging with [11C]PiB in two murine models of AD. In Aim 2, we will quantify and characterize microtubule uptake in brains of the same murine models of AD using [3H]/[11C]MPC-6827. We will perform ex vivo biodistribution, in vitro autoradiography and histopathological assays to correlate microtubule density with routine neurobiomarkers. In Aim 3, we will determine and establish dependency of microtubule imaging uptake to amyloid ? and/or tau levels after therapeutic interventions. We will perform microPET/CT images in the same two murine models of AD, before, during and after the standard treatment protocols with potential therapeutic agents reducing amyloid ? and/or tau levels. In this project, led by an Early Stage Investigator, we hypothesize that we can expand the microtubule scaffold as potential in vivo imaging agents, not only to diagnose AD at an early stage, but also follow the therapeutic utility of the treatments. The PET imaging data generated could be a valuable tool for clinicians to assess AD in several stages of progression and treatment. This project is the first to propose the imaging of microtubules in vivo in AD. If successful, this work will provide a new paradigm to directly probe microtubules in vivo in real time. Our work could markedly enhance precision medicine approaches for treatment of AD and other neurodegenerative diseases.